Skin or mucosal inflammation is often manifested as erythema. Erythema is frequently associated with diaper rash, acne, dermatitis, eczema and other skin or mucosal conditions. Another example of erythema is radiation dermatitis, which is an inflammatory skin reaction associated with prolonged exposure to ionizing radiation.
Radiation dermatitis occurs to some degree in most patients receiving radiation therapy, with or without chemotherapy. In severe cases it leads to discontinuation of radiation therapy. Acute radiation induced dermatitis is one of the most frequent side effects of radiotherapy. The pathoethiological cause for the reaction is linked to massive ROS production which is induced during irradiation treatment (Beckmann and Flohé 1981) and in the course of chemotherapy (Kasapović et al. 2010). This ionizing radiation can lead to acute dermatitis in 95% of patients, whereof in 87% of patients moderate to severe radiodermatitis occurs during or at the end of the treatment (Mc Question M 2006). The severity of the skin reaction ranges from a moderate erythema to edema or deep ulcerations. The occurrence of this reaction depends on aspects associated with the therapy (radiation quality, dose per fraction, cumulative dose, fraction scheme, size of the treatment area, concomitant therapy, pre-radiation, localization of irradiated area) and on aspects associated with the patient (skin type, sensitivity to radiation, concomitant diseases). Pruritus, erythema, skin distension, epitheliolysis, and pain affect not only the quality of life but also pose a risk of an infection of the open wounds. Consequently, this may lead to treatment interruptions or discontinuations of the RTX, and longer deferment of the subsequently planned system therapy. Thus an early detection, precise documentation and treatment of these dermal toxicities are of great importance.
Furthermore, up to now there is no reliable prognostic parameter available to predict the risk to develop radiodermatitis upon radiation therapy. According to historical data, breast size, smoking history, body mass index (BMI) and comorbidities such as diabetes, rheumatoid arthritis and hypertension are under suspicion to be correlated with an increased risk for the development of radiodermatitis in the course of cancer irradiation therapy (Fernando I N et al., Clin Oncol 1996; 8:226-233). However the published data is conflicting. According to a recent single blind randomized phase III trial in breast cancer patients, no association between dermatitis and BMI or breast size were observed (Pinnix C et al., Int J Radiat Oncol Biol Phys 2012 Jul. 15; 83(4):1089-94), also confirmed by our own data. Furthermore, the radiation field size (cm2) and the basic skin color according to the Fitzpatrick Scale (1-2 versus 3-4) did not correlate with the risk to develop grade 2 dermatitis (based on the CTCAE, further described below) according to our own data. However, a prognostic marker would allow to prevent or reduce radiation dermatitis by determining or adapting radiation dose and duration, and also to predict the time until a prophylaxis and/or treatment needs to be given.
So far, erythema is clinically assessed mainly by subjective observation by a physician. For example, the classification system Common Terminology Criteria for Adverse Effects (CTCAE v. 4.03), developed by the Radiation Therapy Oncology Group (RTOG), and the National Cancer Institute (NCI), divides skin reactions and other adverse events into 5 grades, according to the degree of severity. This grading system has already been used in numerous clinical trials. However, the shortcomings of said current clinical classification systems are mainly based on the subjective assessment of the skin condition, which can vary greatly among assessors and may even differ in one assessor in the course of one day or between several days. A further drawback of this method is the classification in only five grades. Thus, minor differences in the skin condition, as needed for clinical comparison of the effectiveness of e.g. topical medication, cannot be sufficiently indicated.
For a more objective assessment of erythema several devices have been used. For example, chromameters have been utilized for analyzing hemoglobin, since skin or mucosal erythema is primarily due to vasodilation and local increases in hemoglobin concentration. Chromameters give values of standardized parameters for color evaluation: L*, a*, b*, with a* being used as an indicator of the “red” content and therefore related to erythema.
Spectrophotometers have also been used for analyzing hemoglobin based on diffuse reflectance spectroscopy, according to which the reflected light from skin is collected and analyzed into its spectral components. Spectral analysis algorithms have been used to calculate chromophore concentrations including oxy- and deoxy-hemoglobin (relating to erythema). Various light reflectance devices such as a Mexameter are also known for giving an erythema index.
The analysis of digital color images of skin has also been utilized for analyzing erythema
Such methods are described for example in U.S. Pat. No. 8,150,501 and in Jung et al 2005, Lasers in Surgery and Medicine 37:186-191 or U.S. Pat. No. 8,150,501 and Jung et al 2004, Lasers in Surgery and Medicine 34:174-181.
Another imaging analysis tool for the assessment of erythema is the DermaVision system from the company OptoBioMed (http://www.optobiomed.co.kr/; see also the patent application KR2003083623).
The wound healing analysis tool (W.H.A.T) is a computer-based method to assess wound healing (see e.g. T. Wild, M. Prinz, N. Fortner, W. Krois, K. Sahora, S. Stremitzer and T. Hoelzenbein (2008). “Digital measurement and analysis of wounds based on colour segmentation”. European Surgery 40(1):5-10; and S. Stremitzer and T. Wild (2007). “Digitate Wundanalyse mit W.H.A.T. (Wound Healing Analyzing Tool): Manual der Wundheilung. 15-22; and http://what-tool.com). The W.H.A.T system is based on certain threshold levels for parameters, such as color, which allow categorization and sizing of wound segments (e.g. wound center, wound border) and thus, allows to document wound healing based on the assessment of the decrease of the size of the central wound area, which is defined by certain threshold parameters.
Nischek et al. (IEEE Transactions on Medical Imaging, vol 16, no 6, 1997) analyse skin erythema using true-color images. Hirotsugu (The Journal of Medical Investigation, vol 44, 1998, pages 121-126) discloses methods for use in measurement of skin color. Document US 2005/030372 A1 (Jung et al.) discloses a method for assessing erythema of a subject.
All of the methods described above are able to identify erythema or skin redness and to define areas of erythema. However, these techniques show substantial deficiencies in the assessment of erythema intensity. In particular, the prior art methods do not allow a reliable quantitative measurement of various grades of inflammation or the differentiation between several intensities of erythema, especially not for rather low or high intensities of erythema. Thus, the methods of the prior art do neither provide a solid measure for erythema and therewith associated cutaneous alterations over the entire range of intensities nor do they offer a innovative computational techniques linking erythema assessment and erythema documentation with the possibility for remote monitoring of individual subjects or subject areas over varying observation periods.
Accordingly, novel objective methods and innovative computational assessment and monitoring tools are urgently needed for reduction of these inter- and intra-observer variability as well as for sensitive and quantitative assessment of the degree of erythema over the entire intensity range and varying observation times.